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Vitamin D target proteins: function and regulation
S Christakos1, F Barletta, M Huening
1Department of Biochemistry, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103, USA. christak@umdnj.edu
Abstract:
Recent findings have indicated that calbindin-D(28k), the first known target of vitamin D action, is present in osteoblasts and protects against TNF and glucocorticoid induced apoptosis of osteoblastic cells. Cytokine mediated destruction of pancreatic beta cells, a cause of insulin dependent diabetes, is also inhibited by calbindin-D(28k). In calbindin-D(28k) transfected pancreatic beta cells free radical formation by cytokines is inhibited by calbindin. Thus, besides its role as a facilitator of calcium diffusion, calbindin has a major role in protecting against cellular degeneration in different cell types. Besides calbindin, the other known pronounced effect of 1,25(OH)(2)D(3) in intestine and kidney is increased synthesis of 25(OH)D(3) 24-hydroxylase (24(OH)ase) which is involved in the catabolism of 1,25(OH)(2)D(3). We have noted that CCAAT enhancer binding protein beta (C/EBPbeta) is induced by 1,25(OH)(2)D(3) in kidney and osteoblastic cells and can enhance the transcriptional response of 24(OH)ase to 1,25(OH)(2)D(3). These studies establish C/EBPbeta as a novel 1,25(OH)(2)D(3) target gene and indicate a role for C/EBPbeta in 24(OH)ase transcription. These studies extend our previous studies related to factors that affect vitamin D receptor (VDR) mediated 24(OH)ase transcription (YY1, TFIIB, CBP) and the effect of signaling pathways on 24(OH)ase transcription and cofactor recruitment.
Insights
Calbindin-D(28k) protects cells from degeneration, including osteoblasts and pancreatic beta cells. CCAAT enhancer binding protein beta (C/EBPbeta) is a new vitamin D target gene involved in regulating 24-hydroxylase transcription.
Area of Science:
- Cell Biology
- Endocrinology
- Molecular Biology
Background:
- Calbindin-D(28k), a vitamin D target, protects osteoblasts and pancreatic beta cells from apoptosis and degeneration.
- 1,25(OH)(2)D(3) also induces 25(OH)D(3) 24-hydroxylase (24(OH)ase), crucial for vitamin D catabolism.
Purpose of the Study:
- To investigate the role of CCAAT enhancer binding protein beta (C/EBPbeta) as a novel vitamin D target gene.
- To determine C/EBPbeta's function in regulating 24(OH)ase transcription.
Main Methods:
- Investigated calbindin-D(28k) expression and function in osteoblasts and pancreatic beta cells.
- Analyzed the induction of C/EBPbeta by 1,25(OH)(2)D(3) in kidney and osteoblastic cells.
- Assessed the effect of C/EBPbeta on 24(OH)ase transcription.
Main Results:
- Calbindin-D(28k) demonstrates a protective role against cellular degeneration beyond calcium transport.
- C/EBPbeta is identified as a novel 1,25(OH)(2)D(3) target gene.
- C/EBPbeta enhances the transcriptional activity of 24(OH)ase in response to 1,25(OH)(2)D(3).
Conclusions:
- Calbindin-D(28k) plays a significant role in cellular protection against degeneration.
- C/EBPbeta is a key regulator in the vitamin D signaling pathway, influencing 24(OH)ase expression.
- These findings expand the understanding of vitamin D receptor-mediated gene transcription and cofactor recruitment.
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